Longitudinal analyses using 18F-Fluorodeoxyglucose positron emission tomography with computed tomography as a measure of COVID-19 severity in the aged, young, and humanized ACE2 SARS-CoV-2 hamster models.

This study compared disease progression of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in three different models of golden hamsters: aged (≈60 weeks old) wild-type (WT), young (6 weeks old) WT, and adult (14-22 weeks old) hamsters expressing the human-angiotensin-converting enzyme 2 (hACE2) receptor. After intranasal (IN) exposure to the SARS-CoV-2 Washington isolate (WA01/2020), 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography with computed tomography (18F-FDG PET/CT) was used to monitor disease progression in near real time and animals were euthanized at pre-determined time points to directly compare imaging findings with other disease parameters associated with coronavirus disease 2019 (COVID-19). Consistent with histopathology, 18F-FDG-PET/CT demonstrated that aged WT hamsters exposed to 105 plaque forming units (PFU) developed more severe and protracted pneumonia than young WT hamsters exposed to the same (or lower) dose or hACE2 hamsters exposed to a uniformly lethal dose of virus. Specifically, aged WT hamsters presented with a severe interstitial pneumonia through 8 d post-exposure (PE), while pulmonary regeneration was observed in young WT hamsters at that time. hACE2 hamsters exposed to 100 or 10 PFU virus presented with a minimal to mild hemorrhagic pneumonia but succumbed to SARS-CoV-2-related meningoencephalitis by 6 d PE, suggesting that this model might allow assessment of SARS-CoV-2 infection on the central nervous system (CNS). Our group is the first to use (18F-FDG) PET/CT to differentiate respiratory disease severity ranging from mild to severe in three COVID-19 hamster models. The non-invasive, serial measure of disease progression provided by PET/CT makes it a valuable tool for animal model characterization.

Effects of the COVID-19 pandemic on hospital admissions and inpatient mortality in Kenya (preprint)

Background: The impact of COVID-19 in Africa remains poorly defined. We sought to describe trends in hospitalisation due to all medical causes, pneumonia-specific admissions, and inpatient mortality in Kenya before and during the first five waves of the COVID-19 pandemic in Kenya. Methods: We conducted a hospital-based observational study of patients admitted to 13 public referral facilities in Kenya from January 2018 to December 2021. The pre-COVID population included patients admitted before 1 March 2020. We fitted time series models to compare observed and predicted trends for each outcome. To estimate the impact of the COVID-19 pandemic we calculated incidence rate ratios (IRR) and corresponding 95% confidence intervals (CI) from negative binomial mixed-effects models. Results: Out of 302,703 patients (range 7453 to 27168) hospitalised across the 13 surveillance sites 84,337 (55.2%) were aged 15 years and older. Compared with the pre-COVID period, hospitalisations declined markedly among adult (IRR 0.68, 95% CI 0.63 to 0.73) and paediatric (IRR 0.67, 95% CI 0.62 to 0.73) patients. Adjusted in-hospital mortality also declined among both adult (IRR 0.83, 95% CI 0.77 to 0.89) and paediatric (IRR 0.85, 95% CI 0.77 to 0.94) admissions. Pneumonia-specific admissions among adults were higher during the pandemic (IRR 1.75, 95% CI 1.18 to 2.59), while the paediatric pneumonia cases were lower than pre-pandemic levels in the first year of the pandemic and elevated in late 2021 (IRR 0.78, 95% CI 0.51 to 1.20). Conclusions: Contrary to initial predictions, the COVID-19 pandemic was associated with lower rates of hospitalisation and in-hospital mortality, despite increased pneumonia admissions among adults. These trends were sustained after the withdrawal of containment measures that resulted in the disruption of essential health services, suggesting a role for additional factors that warrant further investigation.

Impact of COVID-19 on mortality in coastal Kenya: a longitudinal open cohort study (preprint)

Background: There is uncertainty about the mortality impact of the COVID-19 pandemic in Africa because of poor ascertainment of cases and limited national civil vital registration. We analysed excess mortality from 1st January 2020-5th May 2022 in a Health and Demographic Surveillance Study in Coastal Kenya where the SARS-CoV-2 seroprevalence reached 75% among adults in March 2022 despite vaccine uptake of only 17%. Methods: We modelled expected mortality in 2020-2022 among a population of 306,000 from baseline surveillance data between 2010-2019. We calculated excess mortality as the ratio of observed/expected deaths in 5 age strata for each month and for each national wave of the pandemic. We estimated cumulative mortality risks as the total number of excess deaths in the pandemic per 100,000 population. We investigated observed deaths using verbal autopsy. Findings: We observed 16,236 deaths among 3,410,800 person years between 1st January 2010 and 5th May 2022. Across 5 waves of COVID-19 cases during 1st April 2020-16th April 2022, population excess mortality was 4.1% (95% PI -0.2%, 7.9%). Mortality was elevated among those aged [≥]65 years at 14.3% (95% PI 7.4%, 21.6%); excess deaths coincided with wave 2 (wild-type), wave 4 (Delta) and wave 5 (Omicron BA1). Among children aged 1-14 years there was negative excess mortality of -20.3% (95% PI -29.8%, -8.1%). Verbal autopsy data showed a transient reduction in deaths from acute respiratory infections in 2020 at all ages. For comparison with other studies, cumulative excess mortality risk for January 2020-December 2021, age-standardized to the Kenyan population, was 47.5/100,000. Interpretation: Net excess mortality during the pandemic was substantially lower in Coastal Kenya than in many high income countries. However, adults, aged [≥]65 years, experienced substantial excess mortality suggesting that targeted COVID-19 vaccination of older persons may limit further COVID-19 deaths by protecting the residual pool of naive individuals.

Methods to evaluate the impact of SARS-CoV-2 nucleocapsid mutations on antigen detection by rapid diagnostic tests.

Mutations in the nucleocapsid of SARS-CoV-2 may interfere with antigen detection by diagnostic tests. We used several methods to evaluate the effect of various SARS-CoV-2 nucleocapsid mutations on the performance of the Panbio™ and BinaxNOW™ lateral flow rapid antigen tests and a prototype high-throughput immunoassay that utilizes Panbio antibodies. Variant detection was also evaluated by immunoblot and BIAcore™ assay. A panel of 23 recombinant nucleocapsid antigens (rAgs) were produced that included mutations found in circulating SARS-CoV-2 variants, including variants of concern. All mutant rAgs were detected by all assays, at a sensitivity equivalent to wild-type control (Wuhan strain). Thus, using a rAg approach, we found that the SARS-CoV-2 nucleocapsid mutations examined do not directly impact antigen detection or antigen assay performance.

Epidemiological impact and cost-effectiveness analysis of COVID-19 vaccination in Kenya (preprint)

ABSTRACT Background Few studies have assessed the benefits of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection. Methods We conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (> 18 years) population prioritizing roll-out in over 50-year olds (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at $7 per dose and vaccine delivery costs of $3.90-$6.11 per dose. The cost-effectiveness threshold was USD 919. Findings Slow roll-out at 30% coverage largely targets over 50-year-olds and resulted in 54% fewer deaths (8,132(7,914 to 8,373)) than no vaccination and was cost-saving (ICER=US$-1,343 (-1,345 to - 1,341) per DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757 to 872) and 5% (282 (251 to 317) but was not cost-effective, using Kenya’s cost-effectiveness threshold ($ 919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=$-1,607 (-1,609 to -1,604) per DALY averted) compared to slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective. Interpretation With prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective. KEY QUESTIONS What is already known? The COVID-19 pandemic has led to a substantial number of cases and deaths in low-and middle-income countries. COVID-19 vaccines are considered the main strategy of curtailing the pandemic. However, many African nations are still at the early phase of vaccination. Evidence on the cost-effectiveness of COVID-19 vaccines are useful in estimating value for money and illustrate opportunity costs. However, there is a need to balance these economic outcomes against the potential impact of vaccination. What are the new findings? In Kenya, a targeted vaccination strategy that prioritizes those of an older age and is deployed at a rapid rollout speed achieves greater marginal health impacts and is better value for money. Given the existing high-level population protection to COVID-19 due to prior exposure, vaccination of younger adults is less cost-effective in Kenya. What do the new findings imply? Rapid deployment of vaccines during a pandemic averts more cases, hospitalisations, and deaths and is more cost-effective. Against a context of constrained fiscal space for health, it is likely more prudent for Kenya to target those at severe risk of disease and possibly other vulnerable populations rather than to the whole population.

Impact of the COVID-19 epidemic on mortality in rural coastal Kenya (preprint)

Background: The impact of COVID-19 on all-cause mortality in sub-Saharan Africa remains unknown. Methods: We monitored mortality among 306,000 residents of Kilifi Health and Demographic Surveillance System, Kenya, through four COVID-19 waves from April 2020-September 2021. We calculated expected deaths using negative binomial regression fitted to baseline mortality data (2010-2019) and calculated excess mortality as observed-minus-expected deaths. We excluded deaths in infancy because of under-ascertainment of births during lockdown. In February 2021, after two waves of wild-type COVID-19, adult seroprevalence of anti-SARS-CoV-2 was 25.1%. We predicted COVID-19-attributable deaths as the product of age-specific seroprevalence, population size and global infection fatality ratios (IFR). We examined changes in cause of death by Verbal Autopsy (VA). Results: Between April 2020 and February 2021, we observed 1,000 deaths against 1,012 expected deaths (excess mortality -1.2%, 95% PI -6.6%, 5.8%). Based on SARS-CoV-2 seroprevalence, we predicted 306 COVID-19-attributable deaths (a predicted excess mortality of 30.6%) within this period. Monthly mortality analyses showed a significant excess among adults aged [≥]45 years in only two months, July-August 2021, coinciding with the fourth (Delta) wave of COVID-19. By September 2021, overall excess mortality was 3.2% (95% PI -0.6%, 8.1%) and cumulative excess mortality risk was 18.7/100,000. By VA, there was a transient reduction in deaths attributable to acute respiratory infections in 2020. Conclusions: Normal mortality rates during extensive transmission of wild-type SARS-CoV-2 through February 2021 suggests that the IFR for this variant is lower in Kenya than elsewhere. We found excess mortality associated with the Delta variant but the cumulative excess mortality risk remains low in coastal Kenya compared to global estimates.

An observational study of the association between COVID-19 vaccination rates and participation in a vaccine lottery (preprint)

Objectives Are financial incentives from entry in a vaccine lottery associated with a higher probability of vaccination for COVID-19? Design A cross-sectional study with adjustment for covariates using logistic regression Setting October and November 2021, Australia. Participants 2,375 respondents of the Taking the Pulse of the Nation Survey Interventions Participation in the Million Dollar Vaccination Lottery Primary and secondary outcome measures The proportion of respondents who had any vaccination, a first dose only, or second dose compared to all other respondents Results Those who participated in the lottery were 2.27 times more likely to be vaccinated after the lottery opened on October 1st than those who did not. This was driven by those receiving second doses. Lottery participants were 1.38 times more likely to receive their first dose after October 1st and 2.31 times more likely to receive their second dose after October 1st. Conclusions Lottery participation is associated with a higher vaccination rate, with this effect dominated by a higher rate of second doses. There is a smaller insignificant difference for those receiving a first dose, suggesting lotteries may not be as effective at reducing vaccine hesitancy, compared to 'nudging' people to get their second dose more quickly.

COVID-19 Transmission Dynamics Underlying Epidemic Waves in Kenya (preprint)

Policy decisions on COVID-19 interventions should be informed by a local, regional and national understanding of SARS-CoV-2 transmission. Epidemic waves may result when restrictions are lifted or poorly adhered to, variants with new phenotypic properties successfully invade, or when infection spreads to susceptible sub-populations. Three COVID-19 epidemic waves have been observed in Kenya. Using a mechanistic mathematical model we explain the first two distinct waves by differences in contact rates in high and low social-economic groups, and the third wave by the introduction of a new higher-transmissibility variant. Reopening schools led to a minor increase in transmission between the second and third waves. Our predictions of current population exposure in Kenya (∼75% June 1st) have implications for a fourth wave and future control strategies. One Sentence Summary COVID-19 spread in Kenya is explained by mixing heterogeneity and a variant less constrained by high population exposure

Seroprevalence of anti-SARS-CoV-2 IgG antibodies among truck drivers and assistants in Kenya (preprint)

In October 2020, anti-SARS-CoV-2 IgG seroprevalence among truck drivers and their assistants (TDA) in Kenya was 42.3%, higher than among other key populations. TDA transport essential supplies during the COVID-19 pandemic, placing them at increased risk of being infected and of transmitting SARS-CoV-2 infection over a wide geographical area.

The Falling Growth in the Use of Private Hospitals in Australia (preprint)

Australia has a rich public-private mix of financing and provision of healthcare. Since mid-2015, the higher growth in out of pocket costs relative to the growth in wages began to reduce the affordability of private healthcare and marked the start of the drop in private health insurance coverage. Using publicly available data, this paper describes the decline in growth in the utilisation of private hospital care before and after 2015. Growth in the use of elective surgery in private hospitals fell with some indication of increased waiting times in public hospitals, and evidence of doctors spending more of their time in public hospitals rather than in private practice. Private hospitals’ profitability declined, share prices of for-profit private hospital operators fell, and there is evidence of reduced capacity and a fall in long-term investment in the private hospital sector. In 2020, COVID-19 has accelerated these trends and the economic recession is likely to exacerbate reduced affordability of private healthcare. Policy responses should depend on how these changes influence access, cost and quality of care for patients.

Revealing the extent of the COVID-19 pandemic in Kenya based on serological and PCR-test data (preprint)

Policy makers in Africa need robust estimates of the current and future spread of SARS-CoV-2. Data suitable for this purpose are scant. We used national surveillance PCR test, serological survey and mobility data to develop and fit a county-specific transmission model for Kenya. We estimate that the SARS-CoV-2 pandemic peaked before the end of July 2020 in the major urban counties, with 34 - 41% of residents infected, and will peak elsewhere in the country within 2-3 months. Despite this penetration, reported severe cases and deaths are low. Our analysis suggests the COVID-19 disease burden in Kenya may be far less than initially feared. A similar scenario across sub-Saharan Africa would have implications for balancing the consequences of restrictions with those of COVID-19.

The importance of supplementary immunisation activities to prevent measles outbreaks during the COVID-19 pandemic in Kenya (preprint)

BackgroundThe COVID-19 pandemic has disrupted routine measles immunisation and supplementary immunisation activities (SIAs) in most countries including Kenya. We assessed the risk of measles outbreaks during the pandemic in Kenya as a case study for the African Region. MethodsCombining measles serological data, local contact patterns, and vaccination coverage into a cohort model, we predicted the age-adjusted population immunity in Kenya and estimated the probability of outbreaks when contact-reducing COVID-19 interventions are lifted. We considered various scenarios for reduced measles vaccination coverage from April 2020. FindingsIn February 2020, when a scheduled SIA was postponed, population immunity was close to the herd immunity threshold and the probability of a large outbreak was 22% (0-46). As the COVID-19 restrictions to physical contact are lifted, from December 2020, the probability of a large measles outbreak increased to 31% (8-51), 35% (16-52) and 43% (31-56) assuming a 15%, 50% and 100% reduction in measles vaccination coverage. By December 2021, this risk increases further to 37% (17-54), 44% (29-57) and 57% (48-65) for the same coverage scenarios respectively. However, the increased risk of a measles outbreak following the lifting of restrictions on contact can be overcome by conducting an SIA with [≥] 95% coverage in under-fives. InterpretationWhile contact restrictions sufficient for SAR-CoV-2 control temporarily reduce measles transmissibility and the risk of an outbreak from a measles immunity gap, this risk rises rapidly once physical distancing is relaxed. Implementing delayed SIAs will be critical for prevention of measles outbreaks once contact restrictions are fully lifted in Kenya. FundingThe United Kingdoms Medical Research Council and the Department for International Development

MMGB/SA Consensus Estimate of the Binding Free Energy Between the Novel Coronavirus Spike Protein to the Human ACE2 Receptor (preprint)

The ability to estimate protein-protein binding free energy in a computationally efficient via a physics-based approach is beneficial to research focused on the mechanism of viruses binding to their target proteins. Implicit solvation methodology may be particularly useful in the early stages of such research, as it can offer valuable insights into the binding process, quickly. Here we evaluate the potential of the related molecular mechanics generalized Born surface area (MMGB/SA) approach to estimate the binding free energy {Delta}Gbind between the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor. The calculations are based on a recent flavor of the generalized Born model, GBNSR6. Two estimates of {Delta}Gbind are performed: one based on standard bondi radii, and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein-ligand binding. We take the average of the resulting two {Delta}Gbind values as the consensus estimate. For the well-studied Ras-Raf protein-protein complex, which has similar binding free energy to that of the SARS-CoV-2/ACE2 complex, the consensus {Delta}Gbind = -11.8 {+/-} 1 kcal/mol, vs. experimental -9.7 {+/-} 0.2 kcal/mol. The consensus estimates for the SARS-CoV-2/ACE2 complex is {Delta}Gbind = -9.4 {+/-} 1.5 kcal/mol, which is in near quantitative agreement with experiment (-10.6 kcal/mol). The availability of a conceptually simple MMGB/SA-based protocol for analysis of the SARS-CoV-2 /ACE2 binding may be beneficial in light of the need to move forward fast.

UK prevalence of underlying conditions which increase the risk of severe COVID-19 disease: a point prevalence study using electronic health records (preprint)

BackgroundThis study aimed to describe the population at risk of severe COVID-19 due to underlying health conditions across the United Kingdom in 2019. MethodsWe used anonymised electronic health records from the Clinical Practice Research Datalink GOLD to describe the point prevalence on 5 March 2019 of the at-risk population following national guidance. Prevalence for any risk condition and for each individual condition is given overall and stratified by age and region. We repeated the analysis on 5 March 2014 for full regional representation and to describe prevalence of underlying health conditions in pregnancy. We additionally described the population of cancer survivors, and assessed the value of linked secondary care records for ascertaining COVID-19 at-risk status. FindingsOn 5 March 2019, 24{middle dot}4% of the UK population were at risk due to a record of at least one underlying health condition, including 8{middle dot}3% of school-aged children, 19{middle dot}6% of working-aged adults, and 66{middle dot}2% of individuals aged 70 years or more. 7{middle dot}1% of the population had multimorbidity. The size of the at-risk population was stable over time comparing 2014 to 2019, despite increases in chronic liver disease and diabetes and decreases in chronic kidney disease and current asthma. Separately, 1{middle dot}6% of the population had a new diagnosis of cancer in the past five years. InterpretationThe population at risk of severe COVID-19 (aged [≥]70 years, or with an underlying health condition) comprises 18.5 million individuals in the UK, including a considerable proportion of school-aged and working-aged individuals. FundingNIHR HPRU in Immunisation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Pubmed for peer-reviewed articles, preprints, and research reports on the size and distribution of the population at risk of severe COVID. We used the terms (1) risk factor or co-morbidity or similar (2) COVID or SARS or similar and (3) prevalence to search for studies aiming to quantify the COVID-19 at-risk UK population published in the previous year to 19 July 2020, with no language restrictions. We found one study which modelled prevalence of risk factors based on the Global Burden of Disease (which included the UK) and one study which estimated that 8.4 million individuals aged [≥]30 years in the UK were at risk based on prevalence of a subset of relevant conditions in England. There were no studies which described the complete COVID-19 at-risk population across the UK. Added value of this studyWe used a large, nationally-representative dataset based on electronic health records to estimate prevalence of increased risk of severe COVID-19 across the United Kingdom, including all conditions in national guidance. We stratified by age, sex and region to enable regionally-tailored prediction of COVID-19-related healthcare burden and interventions to reduce transmission of infection, and planning and modelling of vaccination of the at-risk population. We also quantified the value of linked secondary care records to supplement primary care records. Implications of all the available evidenceIndividuals at moderate or high risk of severe COVID-19 according to current national guidance (aged [≥]70 years, or with a specified underlying health condition) comprise 18{middle dot}5 million individuals in the United Kingdom, rather than the 8.43 million previously estimated. The 8{middle dot}3% of school-aged children and 19{middle dot}6% of working-aged adults considered at-risk according to national guidance emphasises the need to consider younger at-risk individuals in shielding policies and when re-opening schools and workplaces, but also supports prioritising vaccination based on age and condition-specific mortality risk, rather than targeting all individuals with underlying conditions, who form a large population even among younger age groups. Among individuals aged [≥]70 years, 66{middle dot}2% had at least one underlying health condition, suggesting an age-targeted approach to vaccination may efficiently target individuals at risk of severe COVID-19. These national estimates broadly support the use of Global Burden of Disease modelled estimates and age-targeted vaccination strategies in other countries.

Oligodendrocytes that survive acute coronavirus infection induce prolonged inflammatory responses in the CNS.

Neurotropic strains of mouse hepatitis virus (MHV), a coronavirus, cause acute and chronic demyelinating encephalomyelitis with similarities to the human disease multiple sclerosis. Here, using a lineage-tracking system, we show that some cells, primarily oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), survive the acute MHV infection, are associated with regions of demyelination, and persist in the central nervous system (CNS) for at least 150 d. These surviving OLs express major histocompatibility complex (MHC) class I and other genes associated with an inflammatory response. Notably, the extent of inflammatory cell infiltration was variable, dependent on anatomic location within the CNS, and without obvious correlation with numbers of surviving cells. We detected more demyelination in regions with larger numbers of T cells and microglia/macrophages compared to those with fewer infiltrating cells. Conversely, in regions with less inflammation, these previously infected OLs more rapidly extended processes, consistent with normal myelinating function. Together, these results show that OLs are inducers as well as targets of the host immune response and demonstrate how a CNS infection, even after resolution, can induce prolonged inflammatory changes with CNS region-dependent impairment in remyelination.

Early impact of the COVID-19 pandemic and social distancing measures on routine childhood vaccinations in England, January to April 2020 (preprint)

Electronic health records were used to assess the early impact of COVID-19 on routine childhood vaccination in England to 26 April 2020. MMR vaccination counts fell from February 2020, and in the three weeks after introduction of social distancing measures were 19.8% lower (95% CI -20.7 to -18.9%) than the same period in 2019, before improving in mid-April. A gradual decline in hexavalent vaccination counts throughout 2020 was not accentuated on introduction of social distancing.